ABSTRACT Despite numerous advances in radiotherapy in the past decade, which have effectively enhanced local or locoregional tumor control for many patients, there remains substantial room for improvement. A compelling need in today's era of precision radiotherapy is to further widen the therapeutic window and improve radiation dose conformity to the defined target volume, through technological improvements such as advanced image guidance and motion management. Four-dimensional (4D) imaging and deformable image registration (DIR) are two of the most important tools behind many recent radiotherapy advances, but both are facing significant challenges as the requirement for precision increases. Major limitations of current 4D imaging technology include low temporal/spatial resolution, long image acquisition time, suboptimal tumor contrast, and susceptibility to artifacts caused by irregular breathing. Meanwhile, current DIR techniques focus on morphological similarity but not on the physiological plausibility of the deformation, leading to unrealistic results in various applications. These limitations have significantly hampered the advancement of precision radiotherapy. Our long-term goal is to enhance precision radiotherapy through the development and clinical implementation of advanced image guidance and motion management techniques. The overall objective of this application is to develop, cross-- fertilize, and evaluate two techniques: (a) ultra-quality 4D-MRI and (b) physiologically-based motion modeling, for precision radiotherapy applications. Aim 1 is to develop and optimize a 4D-MRI technique for imaging respiratory motion in the thorax and abdomen at ultra-high spatiotemporal resolution. Aim 2 is to develop a physiologically-based motion modeling method for respiratory motion estimation. Aim 3 is to evaluate ultra- quality 4D-MRI and physiological motion modeling in a patient study. Aim 4 is to construct physiologically realistic 4D digital phantoms for future development of precision radiotherapy applications. Successful completion of these aims will yield powerful image guidance and motion management tools for precision radiotherapy. Such improvements will take precision radiotherapy to a whole new level, by significantly improving radiation dose conformity and opening doors for biological-based treatment adaptation for more effective personalized treatment. The proposed research will have a high impact to the fields of both radiotherapy and medical imaging. It will trigger a wave of extensive studies on a number of new and existing applications such as 4D radiotherapy, radiomics, human digital phantom, function-based dose painting, adaptive planning, etc. Most importantly, it will ultimately improve outcomes for cancer patients by improving our ability to precisely deliver radiation treatment to the target and mitigate radiation-induced injury to normal tissues.